Sleep functional connectivity, hyperexcitability, and cognition in Alzheimer's disease.

INTRODUCTION: Sleep disturbances are common in Alzheimer's disease (AD) and may reflect pathologic changes in brain networks. To date, no studies have examined changes in sleep functional connectivity (FC) in AD or their relationship with network hyperexcitability and cognition. METHODS: We assessed electroencephalogram (EEG) sleep FC in 33 healthy controls, 36 individuals with AD without epilepsy, and 14 individuals with AD and epilepsy. RESULTS: AD participants showed increased gamma connectivity in stage 2 sleep (N2), which was associated with longitudinal cognitive decline. Network hyperexcitability in AD was associated with a distinct sleep connectivity signature, characterized by decreased N2 delta connectivity and reversal of several connectivity changes associated with AD. Machine learning algorithms using sleep connectivity features accurately distinguished diagnostic groups and identified "fast cognitive decliners" among study participants who had AD. DISCUSSION: Our findings reveal changes in sleep functional networks associated with cognitive decline in AD and may have implications for disease monitoring and therapeutic development. HIGHLIGHTS: Brain functional connectivity (FC) in Alzheimer's disease is altered during sleep. Sleep FC measures correlate with cognitive decline in AD. Network hyperexcitability in AD has a distinct sleep connectivity signature.

Cellular resolution contributions to ictal population signals.

OBJECTIVE: The increased amplitude of ictal activity is a common feature of epileptic seizures, but the determinants of this amplitude have not been identified. Clinically, ictal amplitudes are measured electrographically (using, e.g., electroencephalography, electrocorticography, and depth electrodes), but these methods do not enable the assessment of the activity of individual neurons. Population signal may increase from three potential sources: (1) increased synchrony (i.e., more coactive neurons); (2) altered active state, from bursts of action potentials and/or paroxysmal depolarizing shifts in membrane potential; and (3) altered subthreshold state, which includes all lower levels of activity. Here, we quantify the fraction of ictal signal from each source. METHODS: To identify the cellular determinants of the ictal signal, we measured single cell and population electrical activity and neuronal calcium levels via optical imaging of the genetically encoded calcium indicator (GECI) GCaMP. Spontaneous seizure activity was assessed with microendoscopy in an APP/PS1 mouse with focal cortical injury and via widefield imaging in the organotypic hippocampal slice cultures (OHSCs) model of posttraumatic epilepsy. Single cell calcium signals were linked to a range of electrical activities by performing simultaneous GECI-based calcium imaging and whole-cell patch-clamp recordings in spontaneously seizing OHSCs. Neuronal resolution calcium imaging of spontaneous seizures was then used to quantify the cellular contributions to population-level ictal signal. RESULTS: The seizure onset signal was primarily driven by increased subthreshold activity, consistent with either barrages of excitatory postsynaptic potentials or sustained membrane depolarization. Unsurprisingly, more neurons entered the active state as seizure activity progressed. However, the increasing fraction of active cells was primarily driven by synchronous reactivation and not from continued recruitment of new populations of neurons into the seizure. SIGNIFICANCE: This work provides a critical link between single neuron activity and population measures of seizure activity.

Clearing the Smoke: What Protects Smokers from Parkinson's Disease?

The link between smoking and a lower risk of Parkinson's disease (PD) is one of the strongest environmental or lifestyle associations in neuroepidemiology. Growing evidence supports the hypothesis that the association is based on a neuroprotective effect of smoking on PD, despite the plausible alternative that smoking serves as a marker for a proximal protective influence without itself conferring benefit. But how smoking could protect against neurodegeneration in PD is not well understood. Of several candidate molecules and mechanisms that have been nominated, nicotine has received the most attention. However, randomized controlled clinical trials of nicotine in PD have failed to demonstrate benefit on motor endpoints, including the NIC-PD study in which recently diagnosed participants were randomly assigned to placebo or nicotine treatment for 1 year. Given these results, the time is right to evaluate the neuroprotective potential of other molecules and biochemical cascades triggered by smoking. Here, we review the evidence supporting smoking's possible protective effect on PD, compounds in tobacco and smoke that might mediate such benefit, and non-causal classes of explanation, including reverse causation and the prospect of shared genetic determinants of smoking and PD resistance. The therapeutic potential of non-nicotine components of smoke is suggested by studies supporting multiple alternative mechanisms ranging from monoamine oxidase inhibitors to gut microbiome disruption to antioxidant response induction by chronic exposure to low levels of carbon monoxide. Rigorous investigation is warranted to evaluate this molecule and others for disease-preventing and disease-modifying activity in PD models and, if warranted, in clinical trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer's disease model.

BACKGROUND: Alzheimer's disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. METHODS: We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals. Optogenetic stimulation of GABAergic interneurons in the anterior cortex targeted with channelrhodopsin-2 (ChR2) allowed us to examine the role GABAergic interneurons play in sleep deficits. We also examined the effect of optogenetic stimulation on amyloid plaques, neuronal calcium as well as sleep-dependent memory consolidation. In addition, microglial morphological features and functions were assessed using confocal microscopy and flow cytometry. Finally, we performed sleep deprivation during optogenetic stimulation to investigate whether sleep restoration was necessary to slow AD progression. RESULTS: APP-GAD-Cre mice exhibited impairments in sleep architecture including decreased time spent in NREM sleep, decreased delta power, and increased sleep fragmentation compared to nontransgenic (NTG) NTG-GAD-Cre mice. Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP-GAD-Cre animals. Furthermore, it slowed AD progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis, and improving memory function. These changes were accompanied by increased numbers and a morphological transformation of microglia, elevated phagocytic marker expression, and enhanced amyloid ß (Aß) phagocytic activity of microglia. Sleep was necessary for amelioration of pathophysiological phenotypes in APP-GAD-Cre mice. CONCLUSIONS: In summary, our study shows that optogenetic targeting of GABAergic interneurons rescues sleep, which then ameliorates neuropathological as well as behavioral deficits by increasing clearance of Aß by microglia in an AD mouse model.

Association of Plasma Phosphorylated Tau With the Response to Neflamapimod Treatment in Patients With Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: In a proportion of patients, dementia with Lewy bodies (DLB) is associated with Alzheimer disease (AD) copathology, which is linked to accelerated cognitive decline and more extensive cortical atrophy. The objective was to evaluate the relationship between a biomarker of AD copathology, plasma tau phosphorylated at residue 181 (ptau181), and the treatment effects of the p38α kinase inhibitor neflamapimod, which targets the cholinergic degenerative process in DLB. METHODS: The AscenD-LB study was a phase 2a, randomized (1:1), 16-week, placebo-controlled clinical trial of neflamapimod in DLB, the main results of which have been published. After the study was completed (i.e., post hoc), pretreatment plasma ptau181 levels were determined and participants were grouped based on a cutoff for AD pathology of 2.2 pg/mL (established in a separate cohort to identify AD from healthy controls). Clinical outcomes for the comparison of placebo with neflamapimod 40 mg three times daily (TID; the higher and more clinically active of 2 doses studied) were analyzed using mixed models for repeated measures within each subgroup (baseline plasma ptau181 < and ≥2.2 pg/mL). RESULTS: Pretreatment plasma ptau181 levels were determined in eighty-five participants with mild-to-moderate DLB receiving cholinesterase inhibitors, with 45 participants below and 40 above the 2.2 pg/mL cutoff at baseline. In the 16-week treatment period, in the comparison of placebo with neflamapimod 40 mg TID, for all end points evaluated, improvements with neflamapimod treatment were greater in participants below the cutoff, compared with those above the cutoff. In addition, participants below the ptau181 cutoff at baseline showed significant improvement over placebo in an attention composite measure (+0.42, 95% CI 0.07-0.78, p = 0.023, d = 0.78), the Clinical Dementia Rating Scale Sum of Boxes (-0.60, 95% CI -1.04 to -0.06, p = 0.031, d = 0.70), the Timed Up and Go test (-3.1 seconds, 95% CI -4.7 to -1.6, p < 0.001, d = 0.74), and International Shopping List Test-Recognition (+1.4, 95% CI 0.2-2.5, p = 0.024, d = 1.00). DISCUSSION: Exclusion of patients with elevated plasma ptau181, potentially through excluding patients with extensive cortical neurodegeneration, enriches for a patient with DLB population that is more responsive to neflamapimod. More generally, plasma biomarkers of AD copathology at study entry should be considered as stratification variables in DLB clinical trials. TRIAL REGISTRATION INFORMATION: NCT04001517 at ClinicalTrials.gov.

Optogenetic targeting of astrocytes restores slow brain rhythm function and slows Alzheimer's disease pathology.

Patients with Alzheimer's disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP/PS1 mice. The power but not the frequency of astrocytic calcium transients was reduced in APP/PS1 mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

Optogenetic Targeting of Astrocytes Restores Slow Brain Rhythm Function and Slows Alzheimer's Disease Pathology.

Patients with Alzheimer's disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP mice. The power but not the frequency of astrocytic calcium transients was reduced in APP mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

EEG Entropy in REM Sleep as a Physiologic Biomarker in Early Clinical Stages of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is associated with EEG changes across the sleep-wake cycle. As the brain is a non-linear system, non-linear EEG features across behavioral states may provide an informative physiologic biomarker of AD. Multiscale fluctuation dispersion entropy (MFDE) provides a sensitive non-linear measure of EEG information content across a range of biologically relevant time-scales. OBJECTIVE: To evaluate MFDE in awake and sleep EEGs as a potential biomarker for AD. METHODS: We analyzed overnight scalp EEGs from 35 cognitively normal healthy controls, 23 participants with mild cognitive impairment (MCI), and 19 participants with mild dementia due to AD. We examined measures of entropy in wake and sleep states, including a slow-to-fast-activity ratio of entropy (SFAR-entropy). We compared SFAR-entropy to linear EEG measures including a slow-to-fast-activity ratio of power spectral density (SFAR-PSD) and relative alpha power, as well as to cognitive function. RESULTS: SFAR-entropy differentiated dementia from MCI and controls. This effect was greatest in REM sleep, a state associated with high cholinergic activity. Differentiation was evident in the whole brain EEG and was most prominent in temporal and occipital regions. Five minutes of REM sleep was sufficient to distinguish dementia from MCI and controls. Higher SFAR-entropy during REM sleep was associated with worse performance on the Montreal Cognitive Assessment. Classifiers based on REM sleep SFAR-entropy distinguished dementia from MCI and controls with high accuracy, and outperformed classifiers based on SFAR-PSD and relative alpha power. CONCLUSION: SFAR-entropy measured in REM sleep robustly discriminates dementia in AD from MCI and healthy controls.

Disruption of hippocampal neuronal circuit function depends upon behavioral state in the APP/PS1 mouse model of Alzheimer's disease.

The Alzheimer's disease-associated peptide amyloid-beta (Aß) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aß, here we show that Aß aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aß impaired hippocampal theta-gamma phase-amplitude coupling and altered neuronal synchronization with theta. In SWS, Aß reduced cortical slow oscillation (SO) power, the coordination of hippocampal sharp wave-ripples with both the SO and thalamocortical spindles, and the coordination of calcium transients with the sharp wave-ripple. Physostigmine improved Aß-associated hyperactivity in exploratory behavior and hypoactivity in QW and expanded the range of gamma that coupled with theta phase, but exacerbated hypoactivity in exploratory behavior. Together, these findings show that the effects of Aß alone on hippocampal circuit function are profoundly state dependent and suggest a reformulation of therapeutic strategies aimed at Aß induced hyperexcitability.

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.

Serum NFL levels predict progression of motor impairment and reduction in putamen dopamine transporter binding ratios in de novo Parkinson's disease: An 8-year longitudinal study.

Neurofilament light chain (NFL) level in biofluids is a sensitive measure of axonal damage and a promising biomarker in neurodegenerative diseases. In Parkinson's disease (PD), NFL can distinguish PD from other parkinsonian disorders, and NFL concentration is associated with disease severity, risk of progression, and survival. To determine whether serum NFL at baseline in de novo PD predicts motor decline, differentially impacts specific motor features, predicts cognitive decline, and predicts loss of dopamine terminals, here we evaluated 376 de novo PD patients from the PPMI database and analyzed the effect of baseline serum NFL levels on progression over eight years of motor impairment measured with the UPDRS, cognitive function measured with the MoCA, and putamen dopamine transporter (DAT) binding ratio measured with DaTscan. In longitudinal mixed effects models that controlled for age, gender, disease duration, and levodopa equivalent drug dose, higher levels of serum NFL at baseline were associated with greater increases of UPDRS-III and total UPDRS scores, with greater worsening of postural instability and gait disorder (PIGD) scores but not tremor scores over time. In contrast, baseline serum NFL was not associated with significant progression of MoCA scores in this de novo PD cohort. Higher baseline serum NFL was associated with greater reduction of putamen DAT binding ratio over time. Together, these findings show that baseline serum NFL levels predict the rate of motor decline, the accumulation of PIGD clinical features, and the progression of dopamine transporter loss in the early stage of PD.

18F-AV-1451 positron emission tomography in neuropathological substrates of corticobasal syndrome.

Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer's disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P = 0.0011), driven especially by the precentral gyrus (P = 0.011) and pallidum (P < 0.0001), and greater atrophy was seen in subjects compared to control subjects (P = 0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11-0.24, P < 0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35-1.08, P = 0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P < 0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer's disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer's disease is greater and more diffuse.

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

ß-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters.

OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and ß-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years). RESULTS: ß-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual ß-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean ß-glucocerebrosidase activity by 0.85 µmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in ß-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02). CONCLUSIONS: Residual activity of the ß-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. ß-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.

Research criteria for the diagnosis of prodromal dementia with Lewy bodies.

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson's Disease in the Harvard Biomarkers Study.

Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.

Topography of cortical thinning in the Lewy body diseases.

OBJECTIVE: Regional cortical thinning in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) may underlie some aspect of their clinical impairments; cortical atrophy likely reflects extensive Lewy body pathology with alpha-synuclein deposits, as well as associated Alzheimer's disease co-pathologies, when present. Here we investigated the topographic distribution of cortical thinning in these Lewy body diseases compared to cognitively normal PD and healthy non-PD control subjects, explored the association of regional thinning with clinical features and evaluated the impact of amyloid deposition. METHODS: Twenty-one participants with dementia with Lewy bodies (DLB), 16 with Parkinson disease (PD) - associated cognitive impairment (PD-MCI and PDD), and 24 cognitively normal participants with PD underwent MRI, PiB PET, and clinical evaluation. Cortical thickness across the brain and in regions of interest (ROIs) was compared across diagnostic groups and across subgroups stratified by amyloid status, and was related to clinical and cognitive measures. RESULTS: DLB and PD-impaired groups shared a similar distribution of cortical thinning that included regions characteristic of AD, as well as the fusiform, precentral, and paracentral gyri. Elevated PiB retention in DLB and PD-impaired but not in PD-normal participants was associated with more extensive and severe cortical thinning, in an overlapping topography that selectively affected the medial temporal lobe in DLB participants. In DLB, greater thinning in AD signature and fusiform regions was associated with greater cognitive impairment. CONCLUSIONS: The pattern of cortical thinning is similar in DLB and PD-associated cognitive impairment, overlapping with and extending beyond AD signature regions to involve fusiform, precentral, and paracentral regions. Cortical thinning in AD signature and fusiform regions in these diseases reflects cognitive impairment and is markedly accentuated by amyloid co-pathology. Further work will be required to determine whether the distinct topography of cortical thinning in DLB and PD-associated cognitive impairment might have value as a diagnostic and/ or outcome biomarker in clinical trials.

Neuropathologic correlates of amyloid and dopamine transporter imaging in Lewy body disease.

OBJECTIVE: To develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against postmortem neuropathologic findings. METHODS: Four cognitively normal participants with Parkinson disease (PD), 4 with PD with cognitive impairments, and 10 with dementia with Lewy bodies underwent amyloid imaging with [11C]Pittsburgh compound B (PiB) and dopamine transporter (DAT) imaging with [11C]Altropane. All 18 had annual neurologic examinations. All cognitively normal participants with PD developed cognitive impairment before death. Neuropathologic examinations assessed and scored Braak Lewy bodies, Thal distribution of amyloid, Consortium to Establish a Registry for Alzheimer's Disease neuritic amyloid plaques, Braak neurofibrillary tangles, and cerebral amyloid angiopathy, as well as total amyloid plaque burden in the superior frontal, superior parietal, occipital, and inferior temporal cortical regions. PET data were expressed as the standardized uptake value ratio with cerebellar reference. Analyses accounted for the interval between imaging and autopsy. RESULTS: All 18 patients met neuropathologic criteria for Lewy body disease; the DAT concentration was low in each case. All patients with elevated [11C]PiB retention measured in a neocortical aggregate had ß-amyloid deposits at autopsy. [11C]PiB retention significantly correlated with neuritic plaque burden and with total plaque burden. [11C]PiB retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores. Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology. CONCLUSION: Antemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration. [11C]PiB scans accurately reflect cortical amyloid deposits seen at autopsy. These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.

Frequency-dependent exacerbation of Alzheimer's disease neuropathophysiology.

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer's disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of <1 Hz. The power, but not the frequency of slow oscillations is altered in a mouse model of AD. Optogenetic rescue of slow oscillations by increasing activity in cortical pyramidal neurons at the frequency of slow waves restores slow wave power, halts deposition of amyloid plaques and prevents neuronal calcium dysregulation. Here we determined whether driving this circuit at an increased rate would exacerbate the amyloid-dependent calcium dyshomeostasis in transgenic mice. Doubling the frequency of slow waves for one month with optogenetics resulted in increased amyloid beta - dependent disruptions in neuronal calcium homeostasis and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer's disease pathology and should be considered an avenue for clinical treatment of AD patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity - dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.